MCC Tumor-Specific Biomarkers: Basis for Rational Therapy of Merkel Cell Carcinom

描述（由申请人提供）：默克尔细胞癌（MCC）是一种侵袭性人类皮肤癌，每年在美国导致的癌症死亡人数超过慢性骨髓性白血病。其发病率在过去15年中攀升了三倍，达到每年约1500例。直到最近才知道MCC的病因，也没有发现有效的特定化疗。通过基因组筛选，我们发现默克尔细胞多瘤病毒（MCV）是80% MCC的病因。我们发现肿瘤特异性MCV T抗原突变是MCC肿瘤进化的一部分，我们和我们的合作者开发了一个高度特异性和敏感的MCV VLP衣壳ELISA，用于检查MCV感染的自然史，包括危险因素，年龄特异性患病率和原发感染。我们在肿瘤中开发了针对MCV抗原的单克隆抗体。通过敲低研究，我们发现T抗原表达对MCC肿瘤发生至关重要，MCV大T （LT）增加细胞存活癌蛋白（BIRC5a）。在确定survivin是MCC的潜在分子阻塞点后，我们在体外MCC细胞系和小鼠人MCC异种移植物上测试了II期survivin抑制剂YM155。在纳摩尔水平上，YM155作为单剂具有杀伤或延缓MCC生长的活性。临床研究人员目前正在制定一个多中心ECOG方案，以基于这些临床前发现来检查YM155在III/IV期MCC患者中的疗效。该建议是我们的R01的更新，以研究mcv诱导的癌症中的生物标志物。在本提案中，我们寻求利用我们的发现来开发和优化基于MCV感染的MCC个性化治疗：(1)我们将首先研究LT抗原激活survivin的分子基础，以及YM155抑制MCV LT诱导的survivin表达。(2)我们将优化YM155，通过不同剂量、治疗时间和与其他化疗药物联合使用，试图在MCC异种移植模型中诱导持久的肿瘤缓解。(3)我们已经开发了一个小鼠慢病毒T抗原转导表达系统，我们将用它来模拟小鼠MCC的发展，并测量小鼠对MCV T抗原的抗体反应。(4)我们将确定在接受YM155治疗的MCC患者中，患者T抗原抗体能否预测mcv阳性肿瘤的进展或消退。直到最近，世纪挑战集团还是个棘手而神秘的人物。我们的提案表明，在基础发现之后，转化科学的进展可以迅速推进：在这种情况下，自MCV首次被描述以来，在短短3年多的时间里，MCC的进展已经从病因发展到治疗研究。资助这一提议将使我们能够进入下一代实验，在分子水平上确定MCV是如何导致癌症的，如何最好地监测MCC的进展，以及如何最佳地治疗这种病毒诱导的癌症。

DESCRIPTION (provided by applicant): Merkel cell carcinoma (MCC) is an aggressive human skin cancer causing more cancer deaths than chronic myelogenous leukemia in the US each year. Its incidence has climbed three-fold over the past 15 years to ~1500 cases per year. No cause for MCC was known until recently and no specific chemotherapy has been found to be effective. Using a genomic screen, we discovered Merkel cell polyomavirus (MCV) as a cause for 80% of MCC. We discovered tumor-specific MCV T antigen mutations are part of MCC tumor evolution, and we and our collaborators developed a highly specific and sensitive MCV VLP capsid ELISA, which was used to examine the natural history of MCV infection, including risk-factors, age-specific prevalence and primary infection. We developed monoclonal antibodies against MCV antigens in tumors. Through knockdown studies, we showed that T antigen expression is essential for MCC tumorigenesis and that MCV large T (LT) increases cellular survivin oncoprotein (BIRC5a). After identifying survivin to be a potential molecular chokepoint for MCC, we tested the Phase II survivin inhibitor, YM155, on both in vitro MCC cell lines and on human MCC xenografts in mice. YM155 is active as a single agent at nanomolar levels in killing or retarding growth of MCC. A multicenter ECOG protocol is now being developed by clinical investigators to examine the efficacy of YM155 among stage III/IV MCC patients based on these preclinical findings. This proposal is a renewal of our R01 to investigate biomarkers in MCV-induced cancers. In this proposal, we seek to leverage our findings to develop and optimize personalized therapy for MCC based on MCV infection: (1) We will first investigate the molecular basis for LT antigen activation of survivin, as well as YM155 inhibition of MCV LT-induced survivin expression. (2) We will optimize YM155 to try to induce durable tumor remission in MCC xenograft models by varying dose, duration of therapy and use of YM155 in combination with other chemotherapeutic agents. (3) We have developed a mouse lentivirus T antigen transduction expression system, which we will use to model mouse MCC development and to measure murine antibody responses to MCV T antigens. (4) We will determine whether patient antibodies to T antigens predict progression or regression of MCV-positive tumors in MCC patients undergoing YM155 treatment. Until recently MCC was both intractable and enigmatic. Our proposal shows that progress in translational science can rapidly proceed after a fundamental discovery: in this case, progress on MCC has advanced from cause to cure research in just over 3 years since MCV was first described. Funding this proposal will allow us to move onto the next generation of experiments to define at a molecular level how MCV causes cancer, how to best monitor MCC progression and how to optimally treat this virus-induced cancer.